Cardiac arrhythmias associated with structural heart disease are a major cause of morbidity and mortality in the United States and lead to as many as several hundred thousand sudden cardiac deaths each year. Several converging lines of investigation suggest that dysregulation of gap junction mediated intercellular communication, or gap junctional remodeling, contributes to the substrate for cardiac arrhythmias. Myopathic hearts, however, invariably show a multitude of structural and functional perturbations, thus, the unique contribution of gap junctional remodeling to the substrate for cardiac arrhythmias has been difficult to study in isolation from these other contributory factors. The long-term goal of the studies described in this proposal are to determine the specific contribution of dysregulated gap junction mediated intercellular coupling to the formation of the arrhythmogenic substrate and to understand the molecular mechanisms resulting in gap junctional remodeling. Toward this end, we have established several conditional gene-targeted murine models to elucidate the role of the remodeling process in formation of the arrhythmogenic substrate. We have also begun to elucidate mechanisms controlling gap junctional expression and remodeling and discovered that the Wnt signaling cascade acting through a beta-catenin signaling pathway is an important regulatory circuit controlling Cx43 expression in cardiomyocytes. Our specific aims are to establish a direct, causal relationship between gap junctional remodeling, conduction abnormalities and arrhythmogenesis, to determine the role of beta-catenin mediated signaling and its relationship with other signaling pathways in the regulation of Cx43 expression in normal and remodeled murine and canine hearts, and to characterize the role of Wnt signaling in the context of the adult mouse myocardium. Elucidation of the mechanisms regulating gap junctional remodeling and its role in the arrhythmogenic substrate have significant implications for novel pharmacotherapy of lethal cardiac arrhythmias.